Objective: Several studies have highlighted the toxic potential of bisphenol A (BPA), however, BPA release from orthopedic devices remains poorly investigated.Therefore, this study aimed to evaluate BPA levels in the saliva of children treated using Haas expanders. Methods: Twenty-two children of both sexes aged 6–10 years who required rapid maxillary expansion were recruited. One week after placement of elastics to separate the permanent molars, orthodontic bands were adapted, and maxillary impressions were obtained using alginate impression material. Haas expanders were fabricated using a standardized amount of acrylic resin. The bands were cemented using Transbond Plus Light Cure Band (3M).Saliva samples were collected at five time points: before (T0) and 30 minutes (T1), 24 hours (T2), 1 week (T3), and 1 month (T4) after Haas expander installation.BPA levels were measured using ultra-high-performance liquid chromatography coupled with Tandem Mass Spectrometry. The results were evaluated using oneway analysis of variance with Tukey’s post-hoc test (alpha = 5%). Results: BPA levels were below the recommended tolerable daily intake (TDI) at all timepoints;however, salivary BPA levels at T1 (70.324 ng/mL ± 37.05) and at T2 (18.015 ng/mL ± 11.22) were significantly higher compared to that at T0 (0.475 ng/mL ± 0.27) (P < 0.05). Conclusions Salivary BPA levels significantly increased 30 minutes and 24 hours after Haas expander installation and return to baseline values after 1 week. BPA levels did not exceed the TDI, suggesting that the use of Haas expanders may be considered safe concerning BPA exposure in children.

Reliable preclinical models for assessing drug-induced cardiotoxicity are essential to reduce the high rate of drug withdrawals during development. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have emerged as a promising platform for such assessments due to their expression of cardiacspecific ion channels and electrophysiological properties. In this study, we investigated the effects of eight arrhythmogenic drugs—E4031, nifedipine, mexiletine, JNJ303, flecainide, moxifloxacin, quinidine, and ranolazine—on hiPSC-CMs derived from both healthy individuals and a long QT syndrome (LQTS) patient using multielectrode array systems. The results demonstrated dose-dependent changes in field potential duration and arrhythmogenic risk, with LQTS-derived hiPSC-CMs showing increased sensitivity to hERG channel blockers such as E4031. Furthermore, the study highlights the potential of hiPSC-CMs to model disease-specific cardiac responses, providing insights into genetic predispositions and personalized drug responses.Despite challenges related to the immaturity of hiPSC-CMs, their ability to recapitulate human cardiac electrophysiology makes them a valuable tool for preclinical cardiotoxicity assessments. This study underscores the utility of integrating patientderived hiPSC-CMs with advanced analytical platforms, such as multi-electrode array systems, to evaluate drug-induced electrophysiological changes. These findings reinforce the role of hiPSC-CMs in drug development, facilitating safer and more efficient screening methods while supporting precision medicine applications.

Purpose: Metabolic diseases such as diabetes mellitus may play a role in the development and progression of prostate cancer (PC); however, this association remains to be explored in the context of specific PC stages. The objective of this study was to systematically review the evidence for an association between diabetes and overall, early, or advanced PC risk. Materials and Methods: A systematic review with meta-analysis was performed (MEDLINE, EMBASE, and CINAHL) from inception until September 2023. Cohort and case-control studies that assessed PC risk in adult males (≥18 years) associated with type 2 diabetes mellitus or diabetes (if there was no distinction between diabetes type) were included. The Newcastle-Ottawa Scale (NOS) was used to assess study bias; those with NOS<7 were excluded. Evidence certainty was assessed with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) method. Results: Thirty-four studies (n=26 cohorts and n=8 case-controls) were included. Of these, 32 assessed diabetes and all PC stages combined, 12 included early PC stages, and 15 included advanced PC stages. Our meta-analysis showed diabetes had a protective effect against early PC development (n=11, risk ratio [RR]=0.71; 95% confidence interval [CI]=0.61–0.83, I2=84%) but no association was found for combined (n=21, RR=0.95; 95% CI=0.79–1.13, I2=99%) or advanced PC stages (n=15, RR=0.96; 95% CI=0.77–1.18, I2=98%) at diagnosis. According to GRADE, the evidence certainty was very low. Conclusions Diabetes may be protective against early PC stages, yet evidence linking diabetes to risk across all stages, and advanced PC specifically, is less conclusive. High heterogeneity may partially explain discrepancy in findings and was mostly associated with study design, method used for PC diagnosis, and risk measures. Our results may aid risk stratification of males with diabetes and inform new approaches for PC screening in this group, especially considering the reduced sensitivity of prostate-specific antigen values for those with diabetes.

Purpose: Cardiovascular disease (CVD) is more prevalent in men than women, but the mechanisms responsible for this are not fully understood. We aimed to evaluate differences in trimethylamine (TMA), a microbial metabolite and its oxidized form, trimethylamine N-oxide (TMAO), which is thought to promote atherosclerosis, between men and women with coronary heart disease (CHD), using as a reference a non-CVD population. Materials and Methods: This study was carried out within the framework of the CORDIOPREV study (NCT00924937; June 19, 2009), a clinical trial which included 827 men and 175 women with CHD, with a non-CVD population of 375 individuals (270 men and 105 women) as a reference group. Plasma TMA and TMAO were measured by HPLC-MS/MS. The carotid study was ultrasonically assessed bilaterally by the quantification of intima-media thickness of both common carotid arteries (IMT-CC). Results: We found higher TMAO levels and TMAO/TMA ratio in CHD men than CHD women (p=0.034 and p=0.026, respectively). No TMA sex differences were found in CHD patients. The TMA and TMAO levels and TMAO/TMA ratio were lower, and no differences between sexes were found in the non-CVD population. TMAO levels in CHD patients were consistent with higher IMT-CC and more carotid plaques (p=0.032 and p=0.037, respectively) and lower cholesterol efflux in CHD men than CHD women (p<0.001). Conclusions Our results suggest that CHD men have augmented TMAO levels compared with CHD women, presumably as a consequence of higher rate of TMA to TMAO oxidation, which could be associated with CVD, as these sex differences are not observed in a non-CVD population.

The International Severe Asthma Registry (ISAR) was established in 2017 to advance the understanding of severe asthma and its management, thereby improving patient care worldwide. As the first global registry for adults with severe asthma, ISAR enabled individual registries to standardize and pool their data, creating a comprehensive, harmonized dataset with sufficient statistical power to address key research questions and knowledge gaps. Today, ISAR is the largest repository of real-world data on severe asthma, curating data on nearly 35,000 patients from 28 countries worldwide, and has become a leading contributor to severe asthma research. Research using ISAR data has provided valuable insights on the characteristics of severe asthma, its burdens and risk factors, real-world treatment effectiveness, and barriers to specialist care, which are collectively informing improved asthma management. Besides changing clinical thinking via research, ISAR aims to advance real-world practice through initiatives that improve registry data quality and severe asthma care. In 2024, ISAR refined essential research variables to enhance data quality and launched a web-based data acquisition and reporting system (QISAR), which integrates data collection with clinical consultations and enables longitudinal data tracking at patient, center, and population levels. Quality improvement priorities include collecting standardized data during consultations and tracking and optimizing patient journeys via QISAR and integrating primary/secondary care pathways to expedite specialist severe asthma management and facilitate clinical trial recruitment. ISAR envisions a future in which timely specialist referral and initiation of biologic therapy can obviate long-term systemic corticosteroid use and enable more patients to achieve remission.

Background: Neutrophil elastase (NE) has been proposed as a potential biomarker for evaluating the severity and prognosis of bronchiectasis. This study aimed to compare bronchial lavage quantification of NE levels and activities with those of sputum. Methods: A cross-sectional study was conducted in which 24 Vietnamese adults with bronchiectasis were enrolled from June 2023 to August 2023. All participants underwent bronchoscopy to collect bronchial lavage fluid (BLF) from two bronchial locations: one in the region with the greatest bronchial dilatation and one in the normal bronchi or in patients with all lobes affected, the least abnormal lobe (abnormal BLF [ABLF] and normal BLF [NBLF], respectively). Spontaneously expectorated sputum was also collected. Results: Out of 24 cases, the prevalence of mild, moderate and severe bronchiectasis was 14/24 (58.4%), 5/24 (20.8%), and 5/24 (20.8%), respectively. NE concentration and activity were significantly higher in sputum and ABLF than in NBLF (p<0.001). Sputum and ABLF were highly correlated (r=0.841, p<0.001) with no significant difference in NE activity between sputum and ABLF. Higher levels of NE activity were seen in more severe bronchiectasis than in mild bronchiectasis in all samples but were only statistically significant for NE activity in sputum (r=0.418, p=0.042). Conclusion NE activity and concentration are elevated in areas of the lung most affected by bronchiectasis. Sputum is a valid surrogate of pulmonary NE levels, as they correlate strongly with ABLF and confirm in a Vietnamese population the relationship between NE activity and disease severity.

Bronchiectasis has an increasing prevalence and substantial clinical and economic burden. Therefore, physicians should identify patients with bronchiectasis at high risk of disease progression to ensure optimal management in advance. The heterogeneity of bronchiectasis means it is unlikely that any single parameter could identify highrisk patients; therefore, disease severity is usually assessed using validated composite tools, such as the Bronchiectasis Severity Index, FACED, and Bronchiectasis Aetiology Comorbidity Index, to predict long-term outcomes in bronchiectasis. Disease severity, however, implies an advanced process with lung destruction. Earlier intervention may prevent disease progression and improve outcomes. To identify patients at risk, rather than patients with established advanced disease, we need to shift our focus from disease severity to disease activity. Disease activity denotes the activation level of underlying pathophysiological processes and can be measured using clinical presentations and biomarkers. This review discusses a paradigm shift in bronchiectasis management, focusing on disease activity rather than severity, to prevent disease progression.

Background/Aims: Multiple rapid swallows (MRS) is a provocative test during high-resolution esophageal manometry (HRM) to evaluate contraction reserve (CR). This study aims to determine the prevalence of CR in patients with ineffective esophageal motility (IEM) and MRS performed in the upright position, and to assess the ideal number of MRS sequences. Methods: We enrolled adult patients diagnosed with IEM according to the Chicago classification version 4.0 who underwent HRM with 3 MRS sequences. Presence of CR was identified as either: the distal contraction integral (DCI) of the post-MRS sequence exceeding the mean DCI of single swallows (ratio > 1) or the mean DCI of the 3 post-MRS sequences surpassing the mean DCI of single swallows. The occurrence of CR was compared following 1, 2, and 3 MRS sequences. Results: When assessing CR in 57 patients referenced to mean single supine swallow DCI, the pooled prevalence of CR following 1, 2, and 3 MRS sequences was 23/57 (40.4%), 31/57 (54.4%), and 33/57 (57.9%), respectively. More patients had CR after 2 MRS sequences compared to 1 (P < 0.001), but there was no significant difference in CR between 2 and 3 MRS sequences (P = 0.160). More patients had CR after 2 (P = 0.013) and 3 MRS sequences (P = 0.034) when CR was referenced to single upright compared to single supine swallows. Conclusion Among patients with IEM, 58.0% had CR after 3 upright MRS sequences and 2 were adequate to assess CR.

Background/Aims: Buspirone shows promise in treating disorders of gut–brain interaction (DGBIs), particularly functional dyspepsia. However, findings have been mixed. Methods: We systematically searched for prospective studies testing buspirone for any upper gastrointestinal DGBI in 4 databases (Cochrane, PubMed, Scopus, and PsycInfo). The primary outcome was any validated measure of gastrointestinal symptoms. Anxiety, depression and adverse events were secondary outcomes. For randomized controlled trials (RCTs), we performed random-effects meta-analysis of the standardized mean difference (SMD) in post-treatment scores between buspirone and control groups. Risk of bias in RCTs was assessed using the Cochrane Common Mental Disorders Depression Anxiety and Neurosis Group (CCDAN) scale. Results: Ten studies (n = 283) met inclusion criteria, comprising 5 RCTs, 1 N-of-1 trial, 1 cohort, 1 case series, and 2 case reports. Tolerability of buspirone was good. In meta-analysis, buspirone produced a non-significant improvement in functional dyspepsia/gastroparesis symptoms compared to placebo (SMD = –0.14; 95% CI, –0.44 to 0.17; P = 0.39; I 2 = 0%; N studies = 3). Of individual symptoms, buspirone improved bloating severity more than placebo (SMD = –0.41; 95% CI, –0.77 to –0.04; P = 0.03; N studies = 2) but did not improve post-prandial fullness (P = 0.24, N studies = 2) or nausea (P = 0.75, N studies = 2). All RCTs included in the meta-analysis were good quality but most treated for only 4 weeks. Conclusions We found that buspirone did not improve functional dyspepsia symptoms more than placebo, though studies were small. Buspirone showed benefit for bloating severity, albeit based on few studies. Larger and longer trials of buspirone, targeting more defined groups such as patients with bloating, are warranted.

ObjectiveTo explore the effect of Shenge Bushen Capsules （SBC） on sexual development in normal 3-week-old mice. MethodsThe experiment consisted of two parts. In the first part， mice were divided into four groups： The control group and the low， medium， and high-dose SBC groups （234.7， 469.4， 938.7 mg·kg^-1， respectively）. In the second part， mice were divided into four groups： Control group， Pseudostellariae Radix polysaccharide （PRP） group， total flavonoids group， and SBC group， all receiving a dose of 469.4 mg·kg^-1. After 7 days of administration， the vaginal opening of female mice and the descent of testes and scrotum in male mice， as well as the ovarian and testicular organ indices， were observed. After 4 weeks of administration， female and male mice were housed together for 2 days， and the pregnancy rate of females was monitored. After delivery， the pregnant female mice continued receiving the treatment for 4 weeks， and the sexual development of their offspring， including vaginal opening， testicular descent， and organ indices of ovaries and testes， was observed. Serum sex hormones were measured by enzyme-linked immunosorbent assay （ELISA）， and the expression of gonadotropin-releasing hormone （GnRH） and growth hormone （GH） proteins in the hypothalamus was assessed by Western blot. ResultsCompared with the control group， there was no significant effect on the vaginal opening of female mice or the descent of testes in male mice after 7 days of SBC administration. After 4 weeks of administration， the pregnancy rate in the low-dose group was significantly reduced （P<0.05）， but no significant effects were observed in the other groups. The three doses of SBC did not significantly affect the ovarian or testicular organ indices， and there was no significant upregulation in the expression of GnRH or GH in the hypothalamus. The primary component of SBC， Pseudostellariae Radix polysaccharide， significantly reduced the vaginal opening in female mice after 7 days of administration （P<0.05）. After 4 weeks， the serum estradiol levels of non-pregnant female mice were decreased （P<0.05）， but there was no significant effect on the expression of GnRH or GH proteins in the hypothalamus of either male or female mice. Additionally， there were no significant effects on precocious puberty indicators， such as vaginal opening and testicular descent， in the offspring mice. ConclusionSBC does not significantly promote precocious puberty in young mice， and it does not have any noticeable effects on the pregnancy rate of adult mice or the sexual development of their offspring.